1. Field of the Invention
The present invention relates generally to the field of cancer therapy. More particularly, it concerns the use of methoxyestradiol to stimulate p53 expression in tumor cells, thereby inducing programmed cell death.
2. Description of Related Art
Normal tissue homeostasis is achieved by an intricate balance between the rate of cell proliferation and the rate of cell death. Disruption of this balance is thought to be a major deleterious event in the development of cancer. The inhibition of apoptosis (programmed cell death) has been linked to this disruptive event. The effects of such defects are catastrophic, causing over half a million deaths per annum in the United States alone.
The p53 gene is well recognized as a tumor suppressor gene (Montenarh, 1992). There is now considerable evidence linking mutations of p53 in the oncogenesis of many human cancers. There are numerous reports demonstrating that the growth of, for example, colon, glioblastoma, breast cancer, osteosarcoma and lung tumor cells can be suppressed by the expression of wild-type p53.
The introduction of wild-type p53 in a wide variety of p53-mutated cells, using viral delivery methods, has resulted in the expression of the wild-type p53 transgene and a suppression of the malignant phenotype. These observations demonstrate that a high level of expression of wild-type p53 is a desirable course for the treatment of oncogenic malignancy.
As the half-life of p53 is very short, ranging between 15 and 20 minutes, it has proved difficult to increase the expression of exogenous p53 using conventional transfection strategies. The microcellular environment of these cells is such that overexpression of wild-type p53 protein, when achieved, is counteracted by rapid degradation. Hence, delivery of wild-type p53 into cancer cells containing wild-type p53 using conventional viral vectors as a way of reducing tumor growth is at best inefficient. A significant percentage of the cancers retain a wild-type p53 gene, but increasing the expression of these genes likely will suffer from the same limitation.
Therefore, there is a clear need for an approach to sustained induction or increase in wild-type p53 expression in cancer cells to mediate apoptosis in such cancer cells.